Abstract
Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.
| Original language | English |
|---|---|
| Pages (from-to) | 1075-1085 |
| Number of pages | 11 |
| Journal | Kidney International |
| Volume | 81 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 1 2012 |
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Keywords
- cell signaling
- glomerular disease
- podocyte
ASJC Scopus subject areas
- Nephrology
Cite this
Mechanisms of the proteinuria induced by Rho GTPases. / Wang, Liming; Ellis, Mathew J.; Gomez, Jose A.; Eisner, William; Fennell, Walter; Howell, David N.; Ruiz, Phillip; Fields, Timothy A.; Spurney, Robert F.
In: Kidney International, Vol. 81, No. 11, 01.06.2012, p. 1075-1085.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mechanisms of the proteinuria induced by Rho GTPases
AU - Wang, Liming
AU - Ellis, Mathew J.
AU - Gomez, Jose A.
AU - Eisner, William
AU - Fennell, Walter
AU - Howell, David N.
AU - Ruiz, Phillip
AU - Fields, Timothy A.
AU - Spurney, Robert F.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.
AB - Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.
KW - cell signaling
KW - glomerular disease
KW - podocyte
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UR - http://www.scopus.com/inward/citedby.url?scp=84862777971&partnerID=8YFLogxK
U2 - 10.1038/ki.2011.472
DO - 10.1038/ki.2011.472
M3 - Article
C2 - 22278020
AN - SCOPUS:84862777971
VL - 81
SP - 1075
EP - 1085
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 11
ER -